[Federal Register Volume 64, Number 202 (Wednesday, October 20, 1999)]
[Rules and Regulations]
[Pages 56441-56454]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-27159]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 3, 5, 10, 20, 50, 56, 58, 207, 310, 312, 316, 600, 
601, 607, 610, 640, and 660

[Docket No. 98N-0144]
RIN 0910-AB29


Biological Products Regulated Under Section 351 of the Public 
Health Service Act; Implementation of Biologics License; Elimination of 
Establishment License and Product License

AGENCY:  Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY:  The Food and Drug Administration (FDA) is amending the 
biologics regulations to eliminate references to establishment licenses 
and product licenses for all products regulated under the Public Health 
Service Act (the PHS Act). In lieu of filing an establishment license 
application (ELA) and product license application (PLA) in order to 
market a biological product in interstate commerce, a manufacturer will 
file a single biologics license application (BLA) with the agency. Upon 
approval of the BLA, a manufacturer will receive a biologics license to 
market the product in interstate commerce. This action is part of FDA's 
continuing effort to achieve the objectives of the President's 
``Reinventing Government'' initiatives and is intended to reduce 
unnecessary burdens for industry without diminishing public health 
protection. This action implements certain sections of the FDA 
Modernization Act of 1997 (FDAMA).

DATES:  Effective date: The regulation is effective December 20, 1999.

    Compliance Date: Submit all applications with the Form FDA 356h by 
December 20, 1999, and submit any application for licensure as a BLA by 
October 20, 2000.
FOR FURTHER INFORMATION CONTACT:  Robert A. Yetter, Center for 
Biologics Evaluation and Research (CBER) (HFM-10), Food and Drug 
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-827-0373.

SUPPLEMENTARY INFORMATION: 

I. Background

    In the Federal Register of July 31, 1998 (63 FR 40858), FDA 
proposed to amend the biologics and other drug regulations to eliminate 
references to the PLA and ELA and to replace such references with the 
BLA. FDA provided 75 days for comments on the proposed rule. FDA held a 
public meeting, announced in the Federal Register of August 11, 1998 
(63 FR 42773), on September 2, 1998, to discuss the BLA/biologics 
license scheme. FDA also invited the submission of written comments to 
the docket at the public meeting. The transcript of the public meeting 
and written comments to the proposed rule are on file in the Dockets 
Management Branch (HFA-305), 5630 Fishers Lane, rm. 1061, Rockville, MD 
20852.
    Prior to the issuance of the proposed rule, FDA had already 
reviewed its process of licensing biological products and had taken a 
number of actions to reduce the regulatory burdens imposed by the 
licensing process and to make the licensing process more consistent 
with the process for the approval of new drugs. In the Federal Register 
of May 14, 1996 (61 FR 24227), FDA issued a final rule to amend the 
biologics regulations by eliminating the ELA requirement for the 
following specified biotechnology and synthetic biological products 
licensed under section 351 of the PHS Act (42 U.S.C. 262 et seq.): (1) 
Therapeutic deoxyribonucleic acid (DNA) plasmid products; (2) 
therapeutic synthetic peptide products of 40 or fewer amino acids; (3) 
monoclonal antibody products for in vivo use; and (4) therapeutic 
recombinant DNA-derived products. That provision applied only to those 
products that FDA determined under principles articulated in the 
``Intercenter Agreement Between the Center for Drug Evaluation and 
Research and the Center for Biologics Evaluation and Research'' 
(effective on October 31, 1991) to be subject to licensure under 
section 351 of the PHS Act. Thus, upon approval, manufacturers of the 
specified biotechnology and synthetic biological products received a 
single biologics license instead of a product license and an 
establishment license (see Sec. 601.2(c) (21 CFR 601.2(c))).
    In the  Federal Register of July 8, 1997 (62 FR 36558), FDA 
announced the availability of a revised Form FDA 356h entitled 
``Application to Market a New Drug, Biologic, or an Antibiotic Drug for 
Human Use.'' Form FDA 356h was revised as a ``Reinventing Government'' 
initiative to harmonize application procedures between CBER and the 
Center for Drug Evaluation and Research (CDER) as outlined in the 
President's November 1995 National Performance Review Report entitled 
``Reinventing the Regulation of Drugs Made From Biotechnology.'' In the 
notice, FDA advised that applicants for biologics licenses for products 
specified in Sec. 601.2(c) as well as autologous somatic cell therapy 
products could begin to use Form FDA 356h immediately and were required 
to do so beginning January 8, 1998. FDA advised applicants for licenses 
for other biological products that the agency would announce in the 
future when they can voluntarily begin to use and will be required to 
use Form FDA 356h. Upon approval of a BLA submitted on Form FDA 356h, 
FDA will issue a single biologics license. FDA believes that this 
licensing procedure will greatly simplify the application process, 
harmonize application procedures with those of CDER, and reduce 
industry and agency paperwork burdens. As a consequence of this final

[[Page 56442]]

rule, all manufacturers requesting approval to introduce, or deliver 
for introduction, a biological product into interstate commerce must 
use Form FDA 356h to submit a BLA in lieu of separate establishment and 
product applications.
    On November 21, 1997, the President signed into law FDAMA (Pub. L. 
105-115). Section 123 of FDAMA, in pertinent part, amended section 351 
of the PHS Act to specify that a biologics license shall be in effect 
for a biological product prior to such product's introduction into 
interstate commerce. FDAMA thereby statutorily codified FDA's 
administrative BLA/biologics license ``Reinventing Government'' 
initiative. Section 123(a)(1) of FDAMA further states that the 
Secretary of Health and Human Services (the Secretary) (delegated to 
the Commissioner of Food and Drugs at 21 CFR 5.10(a)(5)) shall approve 
a ``biologics license application'' on the basis of a demonstration 
that the biological product that is the subject of the application is 
safe, pure, and potent; and the facility in which the biological 
product is manufactured, processed, packed, or held meets standards 
designed to ensure that the biological product continues to be safe, 
pure, and potent.
    With the consolidation of the ELA's and PLA's into a single BLA, 
the amount of information formerly included in the ELA will be reduced, 
but not eliminated. Much of the information previously reviewed in an 
ELA at FDA will be reviewed by FDA investigators at the manufacturing 
site during a preapproval inspection. Some information formerly 
included in the ELA will now be submitted as ``chemistry, 
manufacturing, and controls'' (CMC) information or under the 
``establishment description'' section of Form FDA 356h. The type and 
amount of information related to the establishment will vary according 
to the specific biological product for which licensure is being 
requested. To describe what information should be included for each 
type of biological product, CBER has prepared a series of guidance 
documents. The following guidance documents are available: (1) 
``Guidance for Industry for the Submission of Chemistry, Manufacturing, 
and Controls Information for a Therapeutic Recombinant DNA-Derived 
Product or a Monoclonal Antibody Product for In Vivo Use'' (61 FR 
56243, October 31, 1996); (2) ``Guidance for the Submission of 
Chemistry, Manufacturing, and Controls Information and Establishment 
Description for Autologous Somatic Cell Therapy Products'' (62 FR 1460, 
January 10, 1997); (3) ``Guidance for Industry for the Submission of 
Chemistry, Manufacturing and Controls Information for Synthetic Peptide 
Substances'' (issued on the internet, November 1994); (4) ``Guidance 
for Industry: Content and Format of Chemistry, Manufacturing and 
Controls and Establishment Description Information for a Vaccine or 
Related Product'' (64 FR 518, January 5, 1999); (5) ``Guidance for 
Industry for the Submission of Chemistry, Manufacturing and Controls 
and Establishment Description Information for Human Plasma-Derived 
Biological Products, Animal Plasma, or Serum-Derived Products'' (64 FR 
7896, February 17, 1999); (6) ``Guidance for Industry: Content and 
Format of Chemistry, Manufacturing and Controls, and Establishment 
Description Information for a Biological In Vitro Diagnostic Product'' 
(64 FR 11023, March 8, 1999); (7) ``Guidance for Industry: On the 
Content and Format of Chemistry, Manufacturing and Controls, and 
Establishment Description Information for an Allergenic Extract or 
Allergen Patch Test'' (64 FR 20006, April 23, 1999); and (8) ``Guidance 
for Industry: For the Submission of Chemistry, Manufacturing and 
Controls, and Establishment Description Information for Human Blood and 
Blood Components Intended for Transfusion or for Further Manufacture 
and for the Completion of the Form FDA 356h Application to Market a New 
Drug, Biologic or an Antibiotic Drug for Human Use'' (64 FR 25049, May 
10, 1999). All of these guidance documents can be downloaded from the 
CBER Guidelines/Guidance document World Wide Web page at ``http://
www.fda.gov/cber/guidelines.htm''. These guidance documents can also be 
obtained by written request to the Office of Communication, Training, 
and Manufacturers Assistance (HFM-40), Center for Biologics Evaluation 
and Research, Food and Drug Administration, 1401 Rockville Pike, 
Rockville, MD 20852-1448. Send one self-addressed adhesive label to 
assist the office in processing your requests. These documents may also 
be obtained by mail by calling the CBER Voice Information System at 1-
800-835-4709 or 301-827-1800, or by fax by calling the FAX Information 
System at 1-888-CBER-FAX or 301-827-3844.

II. Highlights of Proposed Rule

A. Introduction

    FDA licenses biological products under the authority of section 
351(a) of the PHS Act. The PHS Act requires that biological products be 
licensed and be safe, pure, potent, and manufactured in facilities 
designed to ensure that the product continues to be safe, pure, and 
potent. The PHS Act does not specify the license application forms that 
manufacturers must submit to FDA. Except for the biological products 
listed under Sec. 601.2(c), FDA, in the past, has required 
manufacturers to submit a PLA and an ELA (or a PLA and a supplement to 
an existing ELA) for each biological product. Accordingly, upon 
approval, FDA issued two licenses for each product.
    In the proposed rule of July 31, 1998, FDA proposed changes to the 
regulations intended to implement use of the BLA and to implement 
FDAMA. The proposed rule would also change certain definitions to be 
more consistent with FDAMA and eliminate references to the PLA and ELA. 
In the following sections of this document, FDA outlines in greater 
detail the provisions of the proposed rule.

B. Definitions and Deletion of Terms

    In order to reduce any confusion that may result from use of the 
term ``facility'' in section 351 of the PHS Act as amended by FDAMA, 
FDA proposed to amend the definition of ``establishment'' in 
Sec. 600.3(w) (21 CFR 600.3(w)) to clarify that the term has the same 
meaning as ``facility'' in section 351 of the PHS Act. FDA also 
proposed to amend the definition of ``standards'' in Sec. 600.3(n) to 
indicate that the term refers to specifications and procedures 
established in BLA's designed to ensure the continued safety, purity, 
and potency of biological products as well as adherence to 
specifications and procedures in applicable regulations. Establishing 
standards in the BLA is consistent with FDA's previous effort to 
streamline the license review process by deleting certain additional 
standards in the biologics regulations (see 61 FR 40153, August 1, 
1996). This proposed change to Sec. 600.3(n) also would reduce 
confusion in the biologics regulations by establishing consistency with 
FDA's current regulation at 21 CFR 601.5(b)(4) regarding the revocation 
of licenses. FDA proposed to delete the term ``licensee'' as used in 
the biologics regulations in order to reduce confusion and to make 
clear that it is the licensed manufacturer who is responsible for 
compliance with product and establishment requirements. The term 
``licensed manufacturer'' would be inserted in all instances that 
currently read ``licensee.''

[[Page 56443]]

C. Elimination of PLA/ELA and Implementation of BLA

    FDA proposed that the terms ``biologics license'' or ``biologics 
license application'' be substituted in lieu of references to PLA's and 
ELA's and product and establishment licenses in all regulations in 21 
CFR chapter I. In a few instances, references to product and 
establishment licenses would be retained for historical accuracy, e.g., 
Sec. 601.25 (21 CFR 601.25) and 21 CFR 601.26.
    Under the proposed rule, a manufacturer applying for approval to 
market a biological product under section 351 of the PHS Act would 
submit to FDA the appropriate establishment and product information on 
the recently approved Form FDA 356h. Manufacturers would no longer be 
required to submit product or establishment information on one of the 
many different PLA and ELA forms formerly in use. Upon approval of the 
BLA, FDA would issue an approval letter that in general terms states 
that FDA grants the licensed manufacturer a biologics license to 
manufacture the particular biological product. FDA would not issue 
license certificates separate from the approval letter as is current 
agency practice. The approval letter would serve as the functional 
equivalent of a biologics license within the meaning of section 351 of 
the PHS Act.
    Under proposed Sec. 601.2(a), manufacturers would list in the BLA 
the addresses of all locations of manufacture of a biological product. 
FDA believes this will simplify and clarify the licensing processes by 
having necessary establishment information in the BLA and also by 
allowing FDA to approve all locations involved in the manufacture of 
the product without having to issue an establishment license for each 
location.
    Under proposed Sec. 601.9(c), for manufacturers of some biological 
products that would be able to list multiple products in a single BLA, 
(such as blood and blood components and nonstandardized allergenic 
products) and for which FDA will issue a single biologics license to 
the manufacturer for more than one product, FDA would be able to 
license compliant locations and products and exclude noncompliant 
locations.

D. Radioactive Biological Products

    FDA proposed to amend Sec. 601.2(b) to clarify procedures for 
submitting an application for marketing approval for a radioactive 
biological product in order to help ensure consistency with current 
CBER and CDER policies and procedures. The regulation would clarify 
when a manufacturer of a radioactive biological product should submit a 
new drug application (NDA) to CDER or a BLA to CBER. The regulation 
provides that when the biological component of a radioactive coupled 
antibody determines the site of action, normally a BLA would be 
submitted. The regulation will provide sufficient flexibility to take 
into account situations that may arise in the future where the 
scientific issues associated with a radionuclide or other chemically 
synthesized component are more significant than the scientific issues 
associated with the biological component. In such cases, jurisdiction 
will be determined in accordance with principles articulated in the 
``Intercenter Agreement Between the Center for Drug Evaluation and 
Research and the Center for Biologics Evaluation and Research'' of 
October 31, 1991. The proposed changes should not be construed as an 
attempt to address or implement the requirements of section 122 of 
FDAMA, ``Requirements for Radiopharmaceuticals.''
    FDA is also amending Sec. 310.4 (21 CFR 310.4) to make it 
consistent with Sec. 601.2(b). Revisions to the proposed changes to 
Sec. 310.4 have been made for clarity. Certain changes to both 
Sec. 310.4(a) and (b) are necessary in order to make congruous the 
regulations that describe whether CBER or CDER will have primary 
jurisdiction over a radioactive biological product. The amendment to 
Sec. 310.4(b) is prospective and does not alter the approval mechanism 
of any currently approved radioactive biological products that have 
approved NDA's or approved establishment and product licenses. Section 
310.4(a) is amended to make it consistent with Sec. 601.2(b) and to 
clarify that if any biological product has an approved license under 
section 351 of the PHS Act, it is not required to have an approved 
application under section 505 of the Federal Food, Drug, and Cosmetic 
Act (the act) (21 U.S.C. 355).

E. Current Good Manufacturing Practice Requirements

    FDA discussed in the preamble to the proposed rule the 
applicability of current good manufacturing practices (CGMP) 
requirements for biological products. For clarity FDA proposed in 
Sec. 601.2(d) that the CGMP requirements in parts 210, 211, 600, 606, 
and 820 (21 CFR parts 210, 211, 600, 606, and 820) are included, as 
applicable, as part of the establishment requirements for the 
production of a biological product.

III. Comments on the Proposed Rule and FDA Responses

    FDA received two letters of comment in response to the proposed 
rule; one letter from an organization representing the blood and blood 
component industry and another from a manufacturer of biological 
products. Comments received and FDA's responses to the comments are 
discussed below. There were also a few technical changes, to be 
consistent with other changes in this rulemaking or to be consistent 
with statutory language in FDAMA, made to the following regulations: 21 
CFR 50.3(b)(12), 56.102(b)(11), 58.3(e)(13); Secs. 600.81, 601.2, and 
601.21 (21 CFR 601.21). FDA is also revising 21 CFR 601.22 to remove 
wording that was inadvertently added to the regulation in the proposed 
rule that implied that either of two requirements must be met. The 
change eliminates this ambiguity and reinstates the original intent 
that both requirements must be met.
    1. A comment was supportive of the concept of a BLA and use of the 
Form FDA 356h but strongly urged FDA to ensure that the intended 
paperwork reduction and efficiency goals are achieved. The comment 
stated that the simplification of the BLA will be affected by how 
supplemental applications are handled and expressed concern that this 
be adequately addressed. The comment specifically requested that in 
implementing the BLA for blood and blood components that one supplement 
to the BLA be acceptable to report a change in the manufacturing of 
Platelets, Pheresis for all manufacturing locations.
     FDA agrees that it is important to implement the rule in a manner 
that will reduce unnecessary burdens; accordingly the agency is 
implementing several mechanisms for ensuring that this is the case. 
Manufacturers of some biological products will be able to list multiple 
products in a BLA and FDA will issue a single biologics license to the 
manufacturer for more than one product. FDA intends to use this 
approach generally with products that both have been on the market for 
a long period of time and that FDA has considerable knowledge and 
expertise regulating. Currently, only products such as blood and blood 
components and nonstandardized allergenic products will be handled in a 
single BLA. Therefore, a manufacturer of blood and blood components 
will only need to submit one BLA to request approval to market one or 
more blood or blood components, (e.g., Whole Blood, Platelets, Plasma, 
Red Blood Cells, and

[[Page 56444]]

Cryoprecipitated AHF). FDA believes this consolidation of forms and 
submissions will result in a reduced regulatory burden for the blood 
industry because information previously duplicated in the many blood 
and blood component product and establishment applications would be 
submitted only once in the BLA.
     With regard to manufacturing changes, the BLA system will simplify 
submission of supplements to blood and blood component applications. 
Currently, manufacturers desiring to make a single manufacturing change 
that would affect multiple products are required to submit a supplement 
to each individual product and establishment application. Under the 
final rule, a manufacturer would only need to submit one supplement to 
the BLA. For example, under the current PLA/ELA system if a 
manufacturer desired to make a single change to the irradiation 
procedure for its Whole Blood, Red Blood Cells, Platelets, and Plasma 
products manufactured at 3 locations, the manufacturer would be 
required to submit 12 supplements to 4 PLA's, i.e., a separate 
supplement for each blood component manufactured at each location. 
Under the final rule, the manufacturer would only be required to submit 
one supplement to the BLA describing the change for all of the products 
and locations involved. Of course, all data (including applicable 
validation and quality control testing) and information related to all 
the affected products and locations would be expected to be present in 
the supplement. Section 123 of FDAMA states, in part, that the 
Secretary shall approve a BLA on the basis of a demonstration that the 
biological product that is the subject of the application is safe, 
pure, and potent; and the facility in which the biological product is 
manufactured, processed, packed, or held meets standards designed to 
ensure that the biological product continues to be safe, pure, and 
potent. FDA intends to ensure that the final rule will be properly 
implemented and is providing adequate training and management oversight 
to ensure that this happens.
    2. One comment requested the elimination of the use of the Form FDA 
2567, Transmittal of Labels and Circulars, as being duplicative of Form 
FDA 356h.
     FDA disagrees that the form is duplicative. FDA Form 2567 is used 
for any submission of labeling, including promotional labeling. This 
form (OMB Control No. 0910-0039) contains information that is not 
requested in the Form FDA 356h, which is necessary for the adequate 
tracking of labeling submissions to FDA. It provides specific 
identification of the labeling changes, including revision number and 
the type of labeling and provides a check list for the type of changes 
that have been made to the labeling. The form provides a clear, simple 
method for transmitting comments on the labeling to and from the 
manufacturers allowing for quick return of comments and easy 
identification of sequential revisions.
    3. One comment stated that the ``Draft Guidance for Industry: For 
the Submission of Chemistry, Manufacturing and Controls and 
Establishment Description Information for Human Blood and Blood 
Components Intended for Transfusion or for Further Manufacture and For 
the Completion of the Form FDA 356h, `Application to Market a New Drug, 
Biologic or an Antibiotic Drug for Human Use''' (63 FR 37401, July 10, 
1998) requires, for the first time, submission of information regarding 
certain manufacturing standard operating procedures (SOP's), contracts, 
organizational characteristics, organization diagrams, physical plant, 
major equipment, and quality assurance.
     FDA disagrees in part with this comment. Guidance documents do not 
set forth requirements; they provide the agency's current thinking on a 
topic and are nonbinding. A review of SOP's, physical plant 
information, and information on contracts have always been part of an 
assessment of a product's safety, purity, and potency. FDA has the 
authority to require sponsors to submit such information in license 
applications under section 351 of the PHS Act and 21 CFR part 601. In 
the more recent past, FDA has found that inadequate organizational/
managerial oversight and quality assurance problems at firms have 
resulted in firms being out of compliance with the regulations 
applicable to blood and blood components and have been the cause of 
problems leading to significant enforcement action by the agency. FDA 
believes it is important to review information related to the 
managerial/organizational oversight and quality assurance in order to 
ensure that a firm can manufacture products that meet the applicable 
regulatory and statutory requirements. Therefore, FDA will review such 
information as part of the BLA. FDA believes that the burden associated 
with the submission of such information will be minimal. Describing 
organizational aspects can be done through the use of organizational 
charts, and under CGMP regulations, quality assurance is already a 
requirement. The submission of descriptions of such organizations 
should require minimal time for gathering and preparing the 
information. In addition, since other information previously reviewed 
as part of the PLA and ELA will not be required to be included in a 
BLA, FDA estimates that the net effect is no increase in burden or a 
slightly lower burden. For example, information that will no longer be 
submitted in a BLA but should, as appropriate, be available for an 
establishment inspection includes, but is not limited, to such 
information as: (1) Floor plans of facilities, auxiliary facilities and 
self-contained mobile units to show locations of major equipment, hand 
washing facilities and restrooms; (2) Heating, ventilation, and air 
conditioning information; (3) curriculum vitae for physicians, 
physician substitutes, authorized officials and their alternates, and 
managers; (4) ``statement of understanding'' from physicians and 
authorized officials; (5) proof of state licensure of physicians; (6) 
physician substitute certification of training and cardiopulmonary 
resuscitation; (7) supervisor qualifications and number of people 
supervised in the areas of donor suitability, blood collection, 
laboratory processing, and testing; (8) description of any other uses 
for the area where blood collection or processing occurs; (9) 
description of provisions for housekeeping, pest control, and lighting; 
(10) description of records maintenance method, including when they are 
made, how long they are stored, and how they are maintained to permit 
effective recall; and (11) copy of the certificate of incorporation. 
FDA is currently reviewing comments on the draft CMC guidance and will 
consider the comments in any revision made to the ``Draft Guidance for 
Industry: For the Submission of Chemistry, Manufacturing and Controls 
and Establishment Description Information for Human Blood and Blood 
Components Intended for Transfusion or for Further Manufacture and for 
the Completion of the Form FDA 356h, `Application to Market a New Drug, 
Biologic or an Antibiotic Drug for Human Use.'''
    4. One comment supported the proposed revision to Sec. 601.21 but 
recommended that the regulation reference the appropriate section of 
the act applicable to investigational device exemptions.
    FDA agrees with the comment and is amending Sec. 601.21 in the 
final rule to reference section 520(g) of the act (21 U.S.C. 360j(g)) 
that provides for exemption of devices for investigational use.

[[Page 56445]]

    FDA has considered all comments received in response to the 
proposed rule and has determined that the proposed rule should be 
issued as a final rule. Accordingly, FDA is issuing as a final rule 
changes to the biologics regulations that provide for the use of a 
``biologics license application'' and ``biologics license'' for the 
licensure of all products under section 351 of the PHS Act.

IV. Effective Dates and Other Implementation Issues

    FDA is providing a 10-month transition period for implementation of 
the BLA. FDA recognizes that it may take applicants time to switch 
format from PLA's and ELA's to BLA's. Any PLA and ELA for a biological 
product pending on the effective date of these regulations will be 
reviewed as submitted. Notwithstanding the new regulations, new 
submissions by the manufacturer will not be necessary for these 
products. FDA will continue to accept PLA's and ELA's in lieu of a BLA 
until October 20, 2000, of this final rule. However, all applications 
submitted to the agency after the effective date of the final rule will 
be required to include all information indicated in Form FDA 356h in 
order for the application to be considered as complete. PLA's and ELA's 
received after the effective date of the final rule will be 
administratively handled by FDA as a BLA. If the PLA and ELA are 
sufficient for licensure, FDA will issue a biologics license. Any 
manufacturer planning to file a PLA and an ELA during the 10-month time 
period after the effective date of these regulations should contact FDA 
for further guidance.
    Under new Sec. 601.2(e), a manufacturer already holding an approved 
ELA and PLA for a biological product will not be required to file 
supplements to comply with the amended regulations. The approved PLA 
together with portions of the approved ELA relevant to the new 
requirements for the BLA, will be deemed to constitute a BLA under 
section 351 of the PHS Act .

V. Analysis of Impacts

 A. Reduction in Burden

    The use of the harmonized Form FDA 356h for all biological products 
and drugs regulated by CBER and CDER will reduce burden on industry by 
enabling manufacturers to submit applications for biological products 
and drugs in a consistent format.
    Manufacturers intending to introduce biological products into 
interstate commerce will no longer have to prepare a PLA and an ELA to 
submit to the agency for approval. The amount of information that 
manufacturers will need to provide in a BLA will be less than that 
previously required in a PLA and ELA. These changes will enable 
manufacturers to devote fewer resources to submitting documentation to 
the agency. Much of the information previously reviewed in an ELA at 
FDA will be reviewed by FDA investigators at the manufacturing site 
during a preapproval inspection. According to many biological product 
manufacturers, preparation, submission, and approval of a separate PLA 
and ELA for each biological product added substantially to the cost of 
licensing the product.
    The inclusion of reference to parts 210, 211, 600, 606, and 820 in 
the final rule as establishment requirements only serve to clarify 
existing requirements and will not impose any additional burden on 
industry. Biological products regulated under section 351 of the PHS 
Act, are already subject to the CGMP's in parts 600, 606 and, as 
applicable, parts 210 and 211, or 820.

B. Review Under Executive Order 12866 and the Regulatory Flexibility 
Act

    FDA has examined the impact of the final rule under Executive Order 
12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impact; and equity). The agency believes that 
this rule is consistent with the regulatory philosophy and principles 
identified in Executive Order 12866. In addition, the rule is a 
significant regulatory action as defined in Executive Order 12866 and 
is subject to review because it deals with a novel policy issue.
    In accordance with the principles of Executive Order 12866, the 
overall result of the rule will be a substantial reduction in burdens 
on a manufacturer filing an application to market a biological product. 
In addition, FDA anticipates that the rule will facilitate a 
manufacturer's ability to improve its licensed products and methods of 
manufacture by decreasing the burden and cost associated with filing 
applications and supplements.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because, as stated previously, the overall result of 
the rule will be a substantial reduction in reporting burdens, the 
agency certifies that the rule would not have a significant negative 
economic impact on a substantial number of small entities. Therefore, 
under the Regulatory Flexibility Act, no further analysis is required.

C. The Paperwork Reduction Act of 1995

     This final rule contains information collection provisions that 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). The title, description, and the respondent description of the 
information collection provisions are shown below with an estimate of 
the annual reporting burden. Included in the estimate is the time for 
reviewing the instructions, searching existing data sources, gathering 
and maintaining the data needed, and completing and reviewing each 
collection of information.
     Title: Biological Products Regulated Under Section 351 of the 
Public Health Service Act; Implementation of Biologics License; 
Elimination of Establishment License and Product License.
     Description: This final rule revises the regulations regarding the 
procedures for application for approval to market a biological product 
regulated under section 351 of the PHS Act. Under the regulations, a 
manufacturer will submit to FDA the appropriate establishment and 
product information in a single BLA in lieu of filing a separate ELA 
and PLA. Upon approval of the BLA, a manufacturer would receive a 
single biologics license to market the product in interstate commerce.
     Description of Respondents: Manufacturers of biological products.
     The final rule amends the regulations for filing an application to 
market a biological product under Sec. 601.2 to eliminate references to 
establishment licenses and product licenses for all products regulated 
under the PHS Act. The final rule will require biologics manufacturers 
to file a single BLA, rather than either an ELA or PLA, to market a 
biological product. The agency estimates that the total average 
paperwork burden for manufacturers filing one application that 
consolidates the information currently required under both the PLA and 
ELA will decrease approximately 10 percent. The estimate reduces the 
number of annual responses from a combined PLA/BLA/ELA total of 76 to a 
BLA total of 60. This estimate is derived from the total number of 
license applications received

[[Page 56446]]

by FDA in fiscal year (FY) 1997 (76) minus the total number of ELA's 
filed in the same period (17). Based on information provided by 
industry, the time estimated to prepare an application for FDA approval 
to market a product is approximately 1,600 hours. In addition to 
Sec. 601.2, there are other regulations in the final rule that relate 
to certain information to be included in a license application 
including Sec. 640.21(c) (21 CFR 640.21(c)), Sec. 640.22(c) (21 CFR 
640.22(c)), 21 CFR 640.65(a), and 660.21(a)(3) and (d). The burden 
associated with the information collection requirements in these 
regulations is included in the following reporting burden estimate for 
Sec. 601.2.
     The regulation also makes several technical amendments to conform 
the language throughout the biological product regulations to the 
changes made final here for Sec. 601.2. Specifically, the final rule 
makes the following technical term changes: References to product and 
establishment license, and product and establishment applications are 
replaced with ``biologics license'' or ``biologics license 
application;'' and ``licensee'' is replaced with ``licensed 
manufacturer.'' These technical changes do not have an impact on either 
the substantive requirements or the paperwork burden of these 
requirements, each of which carry OMB clearance numbers as follows: 21 
CFR 207.20(c) and 207.21(a) (0910-0045); Secs. 600.80(c)(2) and 600.81 
(0910-0308); Sec. 601.25(b)(3) (0910-0039); 21 CFR 607.20(b) and 607.21 
(0910-0052); and 21 CFR 610.63 and 640.71(b)(1) (0910-0116).
     The following regulations relate to the submission of additional 
information in certain supplements to a BLA. Regulations in 21 CFR 
600.15(b) and 610.53(d) require submission of a request for an 
exemption or modification regarding the temperature requirements during 
shipment and from dating periods, respectively, for certain biological 
products. The preparation of an exemption request is estimated to be 8 
hours; however, no requests were received by the agency under either 
regulation in FY 1997. To account for the rare instance in which a 
request for an exemption may be made, the agency has estimated one 
respondent per year in Table 1 of this document. Section 640.6 (21 CFR 
640.6) requires that an applicant submit a request to make a certain 
modification of Whole Blood. The number of supplements relating to 
Whole Blood filed by an applicant in FY 1997 totaled 74. Because the 
agency could not easily determine the number of supplements filed 
specific to Sec. 640.6, the estimate below is based on last year's 
total number of supplements related to Whole Blood, regardless of 
whether the supplement was filed specific to Sec. 640.6.
     The remaining regulations, Secs. 640.21(c), 640.22(c), 21 CFR 
640.64(c), and 640.74(a) and (b)(2), refer to information that is 
collected under Sec. 601.12, (OMB Control No. 0910-0315) under which 
the collection of information burden is calculated. Moreover, the final 
rule makes only technical changes to these regulations. For example, 
the term ``product license'' is changed to ``biologics license,'' and 
the term ``product licensee'' is changed to ``licensed manufacturer.''
    As required by section 3506(c)(2)(B) of the PRA, FDA provided an 
opportunity for public comment on the information collection provisions 
of the proposed rule (63 FR 40858). One letter of comment on the 
information collection provisions was submitted to OMB. Most of the 
comments submitted to OMB were the same as those submitted directly to 
FDA in response to the proposed rule. FDA's responses to these comments 
are found above in section III of this document. Responses to 
additional comments in the letter received by OMB that were not 
addressed previously are addressed in the following paragraphs.
    1. A comment pointed out that few new BLA's for blood and blood 
components will be submitted to the agency. More frequently changes to 
already approved applications are submitted as supplements. These 
supplements will now use Form FDA 356h for submission to the agency. 
The comment stated if Form FDA 356h is merely substituted for the 
current forms and manufacturers must continue to file a supplement for 
each product at each location, the paperwork will actually increase 
because of the increased CMC and establishment requirements.
    FDA agrees that few new BLA's for blood and blood components are 
submitted to the agency. However, FDA disagrees that the burden will 
increase. Previously, manufacturers desiring to make a single 
manufacturing change that would affect multiple products were required 
to submit a supplement to each individual product and establishment 
application. Under this final rule a manufacturer would only need to 
submit one supplement to the BLA. For example, under the current PLA/
ELA system, if a manufacturer desired to make a single change to the 
irradiation procedure for its Whole Blood, Red Blood Cells, Platelets, 
and Plasma products manufactured at 3 locations, the manufacturer would 
be required to submit 12 supplements to 4 PLA's. Under the proposed BLA 
system, the manufacturer would only be required to submit one 
supplement to the BLA describing the change for all of the products and 
locations involved. Therefore, fewer supplements should be submitted by 
applicants. The size of the decrease in supplements will depend on how 
the applicant bundles the submissions. At the time of submission of a 
supplement, FDA expects that all data and information pertinent to the 
supplement be present or the FDA may refuse to file the application 
(see the guidance entitled ``Center for Biologics Evaluation and 
Research (CBER): Refusal to File (RTF) Guidance for Product License 
Applications (PLA's) and Establishment License Applications (ELA's)'' 
(58 FR 38770, July 20, 1993)). Therefore, if an applicant wishes to 
submit a change affecting multiple locations in one supplement, and all 
data and information supporting the change at those locations are 
present in the supplement, FDA will accept such a submission. FDA, 
therefore, estimates that there will be an overall reduction in burden 
associated with this final rule.
    2. Another comment stated that the number of respondents and 
supplement submissions, and the hours per submission were severely 
underestimated by FDA. The comment expressed concern that FDA was 
unable to specifically enumerate the number of submissions made under 
Sec. 640.6 and suggested that this was ``indicative of a larger 
problem.'' The comment described FDA's approach to burden estimates as 
disturbing for other reasons such as not addressing supplements for 
products other than Whole Blood, and because the agency's internal 
tracking, accounting, and documentation systems may be inadequate. The 
comment stated that FDA had trouble distinguishing between supplemental 
license applications submitted under Secs. 640.6 and 601.12. For the 
purposes of burden hour development, the distinction between 
supplements submitted under Sec. 640.6 and those under Sec. 601.12 is 
somewhat artificial because the burden for the regulated community to 
prepare the supplement is identical regardless of the section under 
which such information is submitted.
    The comment has misinterpreted the estimate. In preparing this 
burden estimate, FDA estimated the burden for those sections of the 
regulations being amended, including Sec. 640.6. No changes in 
Sec. 601.12 were included in this rulemaking, therefore FDA has not 
estimated the burden of this section which already has an approved OMB 
control number (0910-0315). The burden associated with the preparation 
of supplemental applications is also

[[Page 56447]]

included in the estimate for Sec. 601.12 and is outside the scope of 
this rule. Since Sec. 640.6 applies specifically to Whole Blood, an 
estimate as seen in Table 1 of this document is limited to only Whole 
Blood submissions and the associated reporting burden hours. The number 
of respondents reflects the number of FY 1997 supplements submitted 
specifically for Whole Blood, and the 8 hours is an accurate estimate 
for this type of submission. For purposes of carrying out its 
obligations for the review of applications, FDA continues to believe 
that it is unnecessary to keep separate track of those applications 
submitted under Sec. 640.6, because review of these supplemental 
applications is not different from other supplemental applications 
submitted under Sec. 601.12. Because FDA's current tracking system does 
not allow a search of the data base that would identify accurately the 
number of Whole Blood supplements submitted under Sec. 640.6, FDA 
looked at the number of all supplements related only to Whole Blood, 
which is the scope of this regulation, and conservatively estimated the 
burden to account for more rather than fewer burden hours. Therefore, 
the estimated burden hours are likely to be higher than those that may 
actually occur.

                                  Table 1.--Estimated Annual Reporting Burden1
----------------------------------------------------------------------------------------------------------------
                                                      Annual
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours
                                    Respondents      Response        Responses       Response
----------------------------------------------------------------------------------------------------------------
601.2                                  60               1              60           1,600          96,000
600.15(b)                               1               1               1               8               8
610.53(d)                               1               1               1               8               8
640.6                                  74               1              74               8             592
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    The information collection provisions of the final rule have been 
submitted to OMB for review. Prior to the effective date of the final 
rule, FDA will publish a document in the Federal Register announcing 
OMB's decision to approve, modify, or disapprove the information 
collection provisions in the final rule. An agency may not conduct or 
sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB control number.

D. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

List of Subjects

21 CFR Part 3

    Administrative practice and procedure, Biologics, Drugs, Medical 
devices.

21 CFR Part 5

    Authority delegations (Government agencies), Imports, Organization 
and functions (Government agencies).

21 CFR Part 10

    Administrative practice and procedure, News media.

21 CFR Part 20

    Confidential business information, Courts, Freedom of information, 
Government employees.

21 CFR Part 50

    Human research subjects, Prisoners, Reporting and recordkeeping 
requirements, Safety.

21 CFR Part 56

    Human research subjects, Reporting and recordkeeping requirements, 
Safety.

21 CFR Part 58

    Laboratories, Reporting and recordkeeping requirements.

21 CFR Part 207

    Drugs, Reporting and recordkeeping requirements.

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical 
research, Reporting and recordkeeping requirements, Safety.

21 CFR Part 316

    Administrative practice and procedure, Drugs, Reporting and 
recordkeeping requirements.

21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

21 CFR Part 607

    Blood.

21 CFR Parts 610 and 660

    Biologics, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 640

    Blood, Labeling, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and authority delegated to the Commissioner 
of Food and Drugs, 21 CFR parts 3, 5, 10, 20, 50, 56, 58, 207, 310, 
312, 316, 600, 601, 607, 610, 640, and 660 are amended as follows:

PART 3--PRODUCT JURISDICTION

    1. The authority citation for 21 CFR part 3 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f, 
360h-360j, 360gg-360ss, 371(a), 379e, 381, 394; 42 U.S.C. 216, 262.

    2. Section 3.2 is amended by revising paragraph (k) to read as 
follows:


Sec. 3.2   Definitions.

* * * * *
    (k) Premarket review includes the examination of data and 
information in an application for premarket review described in 
sections 505, 510(k), 513(f), 515, or 520(g) or 520(l) of the act or 
section 351 of the Public Health Service Act of data and information 
contained in any investigational new drug (IND) application, 
investigational device exemption (IDE), new drug application (NDA), 
biologics license application, device premarket notification, device 
reclassification petition, and premarket approval application (PMA).
* * * * *

[[Page 56448]]

PART 5--DELEGATIONS OF AUTHORITY AND ORGANIZATION

    3. The authority citation for 21 CFR part 5 continues to read as 
follows:

    Authority:  5 U.S.C. 504, 552, App. 2; 7 U.S.C. 138a, 2271; 15 
U.S.C. 638, 1261-1282, 3701-3711a; 15 U.S.C. 1451-1461; 21 U.S.C. 
41-50, 61-63, 141-149, 321-394, 467f, 679(b), 801-886, 1031-1309; 35 
U.S.C. 156; 42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263, 
264, 265, 300u-300u-5, 300aa-1; 1395y, 3246b, 4332, 4831(a), 10007-
10008; E.O. 11921, 41 FR 24294, 3 CFR, 1977 Comp., p. 124-131; E.O. 
12591, 52 FR 13414, 3 CFR, 1988 Comp., p. 220-223.

    4. Section 5.58 is amended by revising paragraph (a)(3) to read as 
follows:


Sec. 5.58   Orphan products.

    (a) * * *
    (3) Applications for biologics licenses for biological products; or
* * * * *
    5. Section 5.67 is amended by revising paragraphs (a), (b), and (c) 
to read as follows:


Sec. 5.67   Issuance of notices of opportunity for a hearing on 
proposals for denial of approval of applications for licenses or 
revocation of licenses and certain notices of revocation of licenses.

* * * * *
    (a) Notices of opportunity for a hearing on proposals to deny 
approval or filing of applications for biologics licenses under 
Sec. 601.4(b) of this chapter.
    (b) Notices of opportunity for a hearing on proposals to revoke 
biologics licenses under Sec. 601.5(b) of this chapter.
    (c) Notices of revocation, at the manufacturer's request, of 
biologics licenses under Secs. 601.5(a) and 601.8 of this chapter.
* * * * *

 PART 10--ADMINISTRATIVE PRACTICES AND PROCEDURES

    6. The authority citation for 21 CFR part 10 continues to read as 
follows:

    Authority: 5 U.S.C. 551-558, 701-706; 15 U.S.C. 1451-1461; 21 
U.S.C. 141-149, 321-397, 467f, 679, 821, 1034; 28 U.S.C. 2112; 42 
U.S.C. 201, 262, 263b, 264.

    7. Section 10.50 is amended by revising paragraph (c)(19) to read 
as follows:


Sec. 10.50   Promulgation of regulations and orders after an 
opportunity for a formal evidentiary public hearing.

* * * * *
    (c) * * *
    (19) Section 351(a) of the Public Health Service Act on a biologics 
license for a biological product.
* * * * *

 PART 20--PUBLIC INFORMATION

    8. The authority citation for 21 CFR part 20 continues to read as 
follows:

    Authority:  5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531-2582; 
21 U.S.C. 321-393, 1401-1403; 42 U.S.C. 241, 242, 242a, 242l, 242n, 
243, 262, 263, 263b-263n, 264, 265, 300u-300u-5, 300aa-1.

    9. Section 20.100 is amended by revising paragraph (c)(24) to read 
as follows:


Sec. 20.100   Applicability; cross-reference to other regulations.

* * * * *
    (c) * * *
    (24) Applications for biologics licenses for biological products, 
in Sec. 601.51 of this chapter.
* * * * *

PART 50--PROTECTION OF HUMAN SUBJECTS

    10. The authority citation for 21 CFR part 50 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 346, 346a, 348, 352, 353, 355, 360, 
360c-360f, 360h-360j, 371, 379e; 42 U.S.C. 216, 241, 262, 263b-263n.

    11. Section 50.3 is amended by revising paragraph (b)(12) to read 
as follows:


Sec. 50.3   Definitions.

* * * * *
    (b) * * *
    (12) An application for a biologics license, described in part 601 
of this chapter.
* * * * *

PART 56--INSTITUTIONAL REVIEW BOARDS

    12. The authority citation for 21 CFR part 56 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 346, 346a, 348, 351, 352, 353, 355, 
360, 360c-360f, 360h-360j, 371, 379e, 381; 42 U.S.C. 216, 241, 262, 
263b-263n.

    13. Section 56.102 is amended by revising paragraph (b)(11) to read 
as follows:


Sec. 56.102  Definitions.

* * * * *
    (b) * * *
    (11) An application for a biologics license, described in part 601 
of this chapter.
* * * * *

PART 58--GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY 
STUDIES

    14. The authority citation for 21 CFR part 58 continues to read as 
follows:

    Authority: 21 U.S.C. 342, 346, 346a, 348, 351, 352, 353, 355, 
360, 360b-360f, 360h-360j, 371, 379e, 381; 42 U.S.C. 216, 262, 263b-
263n.

    15. Section 58.3 is amended by revising paragraph (e)(13) to read 
as follows:
* * * * *
    (e) * * *
    (13) An application for a biologics license, described in part 601 
of this chapter.
* * * * *

PART 207--REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS 
IN COMMERCIAL DISTRIBUTION

    16. The authority citation for 21 CFR part 207 continues to read as 
follows:

    Authority:  21 U.S.C. 331, 351, 352, 355, 360, 360b, 371, 374; 
42 U.S.C. 262.

    17. Section 207.20 is amended by revising paragraph (c) to read as 
follows:


Sec. 207.20   Who must register and submit a drug list.

* * * * *
    (c) Before beginning manufacture or processing of a drug subject to 
one of the following applications, an owner or operator of an 
establishment is required to register before the agency approves it: A 
new drug application, a new animal drug application, a medicated feed 
application, or a biologics license application.
* * * * *
    18. Section 207.21 is amended by revising the second sentence of 
paragraph (a) to read as follows:


Sec. 207.21   Times for registration and drug listing.

    (a) * * * If the owner or operator of the establishment has not 
previously entered into such an operation, the owner or operator shall 
register within 5 days after submitting a new drug application, new 
animal drug application, medicated feed application, or a biologics 
license application. * * *
* * * * *

PART 310--NEW DRUGS

    19. The authority citation for 21 CFR part 310 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, 
263b-263n.

    20. Section 310.4 is revised to read as follows:


Sec. 310.4   Biologics; products subject to license control.

    (a) If a drug has an approved license under section 351 of the 
Public Health

[[Page 56449]]

Service Act (42 U.S.C. 262 et seq.) or under the animal virus, serum, 
and toxin law of March 4, 1913 (21 U.S.C. 151 et seq.), it is not 
required to have an approved application under section 505 of the act.
    (b) To obtain marketing approval for radioactive biological 
products for human use, as defined in Sec. 600.3(ee) of this chapter, 
manufacturers must comply with the provisions of 601.2(b) of this 
chapter.
    21. Section 310.503 is amended by revising the first sentence of 
paragraph (b) to read as follows:


Sec. 310.503   Requirements regarding certain radioactive drugs.

* * * * *
    (b) It is the opinion of the Nuclear Regulatory Commission, and the 
Food and Drug Administration that this exemption should not apply for 
certain specific drugs and that these drugs should be appropriately 
labeled for uses for which safety and effectiveness can be demonstrated 
by new drug applications or through licensing under the Public Health 
Service Act (42 U.S.C. 262 et seq.) in the case of biologics. * * *
* * * * *

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

    22. The authority citation for 21 CFR part 312 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371; 42 
U.S.C. 262.

    23. Section 312.3 is amended in paragraph (b) by revising the 
definition for Marketing application to read as follows:


Sec. 312.3   Definitions and interpretations.

* * * * *
    (b) * * *
    Marketing application means an application for a new drug submitted 
under section 505(b) of the act or a biologics license application for 
a biological product submitted under the Public Health Service Act.
* * * * *

PART 316--ORPHAN DRUGS

    24. The authority citation for 21 CFR part 316 continues to read as 
follows:

    Authority: 21 U.S.C. 360aa, 360bb, 360cc, 360dd, 371.

    25. Section 316.3 is amended by revising paragraph (b)(9) to read 
as follows:


Sec. 316.3   Definitions.

* * * * *
    (b) * * *
    (9)  Marketing application means an application for approval of a 
new drug filed under section 505(b) of the act or an application for a 
biologics license submitted under section 351 of the Public Health 
Service Act (42 U.S.C. 262).
* * * * *

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    26. The authority citation for 21 CFR part 600 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, 
374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.

    27. Section 600.3 is amended by revising paragraphs (n) and (w) to 
read as follows:


Sec. 600.3   Definitions.

* * * * *
    (n) The word standards means specifications and procedures 
applicable to an establishment or to the manufacture or release of 
products, which are prescribed in this subchapter or established in the 
biologics license application designed to insure the continued safety, 
purity, and potency of such products.
* * * * *
    (w) Establishment has the same meaning as ``facility'' in section 
351 of the Public Health Service Act and includes all locations.
* * * * *
    28. Section 600.15 is amended by revising paragraph (b) to read as 
follows:


Sec. 600.15   Temperatures during shipment.

* * * * *
    (b) Exemptions. Exemptions or modifications shall be made only upon 
written approval, in the form of a supplement to the biologics license 
application, approved by the Director, Center for Biologics Evaluation 
and Research.
    29. Section 600.21 is amended by revising the first sentence to 
read as follows:


Sec. 600.21   Time of inspection.

    The inspection of an establishment for which a biologics license 
application is pending need not be made until the establishment is in 
operation and is manufacturing the complete product for which a 
biologics license is desired. * * *
    30. Section 600.80 is amended by revising the first sentence of 
paragraph (b), the first and second sentences of paragraph (c)(2)(i), 
and by revising paragraphs (g) and (j) to read as follows:


Sec. 600.80   Postmarketing reporting of adverse experiences.

* * * * *
    (b) Review of adverse experiences. Any person having a biologics 
license under Sec. 601.20 of this chapter shall promptly review all 
adverse experience information pertaining to its product obtained or 
otherwise received by the licensed manufacturer from any source, 
foreign or domestic, including information derived from commercial 
marketing experience, postmarketing clinical investigations, 
postmarketing epidemiological/surveillance studies, reports in the 
scientific literature, and unpublished scientific papers. * * *
* * * * *
    (c) * * *
    (2) Periodic adverse experience reports. (i) The licensed 
manufacturer shall report each adverse experience not reported under 
paragraph (c)(1)(i) of this section at quarterly intervals, for 3 years 
from the date of issuance of the biologics license, and then at annual 
intervals. The licensed manufacturer shall submit each quarterly report 
within 30 days of the close of the quarter (the first quarter beginning 
on the date of issuance of the biologics license) and each annual 
report within 60 days of the anniversary date of the issuance of the 
biologics license. * * *
* * * * *
    (g) Multiple reports. A licensed manufacturer should not include in 
reports under this section any adverse experience that occurred in 
clinical trials if they were previously submitted as part of the 
biologics license application. If a report refers to more than one 
biological product marketed by a licensed manufacturer, the licensed 
manufacturer should submit the report to the biologics license 
application for the product listed first in the report.
* * * * *
     (j) Revocation of biologics license. If a licensed manufacturer 
fails to establish and maintain records and make reports required under 
this section with respect to a licensed biological product, FDA may 
revoke the biologics license for such a product in accordance with the 
procedures of 601.5 of this chapter.
* * * * *
    31. Section 600.81 is amended by revising the first sentence to 
read as follows:


Sec. 600.81   Distribution reports.

    The licensed manufacturer shall submit information about the 
quantity of the product distributed under the biologics license, 
including the quantity distributed to distributors. * * *

[[Page 56450]]

PART 601--LICENSING

    32. The authority citation for 21 CFR part 601 continues to read as 
follows:

    Authority:  15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216, 
241, 262, 263; sec.122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C. 
355 note).

Sec. 601.1   [Removed]

    33. Section 601.1  Two forms of licenses is removed.
    34. Section 601.2 is revised to read as follows:


Sec. 601.2   Applications for biologics licenses; procedures for 
filing.

    (a) General. To obtain a biologics license under section 351 of the 
Public Health Service Act for any biological product, the manufacturer 
shall submit an application to the Director, Center for Biologics 
Evaluation and Research, on forms prescribed for such purposes, and 
shall submit data derived from nonclinical laboratory and clinical 
studies which demonstrate that the manufactured product meets 
prescribed requirements of safety, purity, and potency; with respect to 
each nonclinical laboratory study, either a statement that the study 
was conducted in compliance with the requirements set forth in part 58 
of this chapter, or, if the study was not conducted in compliance with 
such regulations, a brief statement of the reason for the 
noncompliance; statements regarding each clinical investigation 
involving human subjects contained in the application, that it either 
was conducted in compliance with the requirements for institutional 
review set forth in part 56 of this chapter; or was not subject to such 
requirements in accordance with Sec. 56.104 or Sec. 56.105, and was 
conducted in compliance with requirements for informed consent set 
forth in part 50 of this chapter. A full description of manufacturing 
methods; data establishing stability of the product through the dating 
period; sample(s) representative of the product for introduction or 
delivery for introduction into interstate commerce; summaries of 
results of tests performed on the lot(s) represented by the submitted 
sample(s); specimens of the labels, enclosures, and containers, and if 
applicable, any Medication Guide required under part 208 of this 
chapter proposed to be used for the product; and the address of each 
location involved in the manufacture of the biological product shall be 
listed in the biologics license application. The applicant shall also 
include a financial certification or disclosure statement(s) or both 
for clinical investigators as required by part 54 of this chapter. An 
application for a biologics license shall not be considered as filed 
until all pertinent information and data have been received from the 
manufacturer by the Center for Biologics Evaluation and Research. The 
applicant shall also include either a claim for categorical exclusion 
under Sec. 25.30 or Sec. 25.31 of this chapter or an environmental 
assessment under Sec. 25.40 of this chapter. In lieu of the procedures 
described in this paragraph, applications for radioactive biological 
products shall be handled as set forth in paragraph (b) of this 
section. The applicant, or the applicant's attorney, agent, or other 
authorized official shall sign the application. An application for any 
of the following specified categories of biological products subject to 
licensure shall be handled as set forth in paragraph (c) of this 
section:
    (1) Therapeutic DNA plasmid products;
    (2) Therapeutic synthetic peptide products of 40 or fewer amino 
acids;
    (3) Monoclonal antibody products for in vivo use; and
    (4) Therapeutic recombinant DNA-derived products.
     (b) Radioactive biological products. To obtain marketing approval 
for a radioactive biological product, as defined in Sec. 600.3(ee) of 
this chapter, the manufacturer of such product shall comply with the 
following:
    (1) An applicant for a radioactive coupled antibody, which means a 
product that consists of an antibody component coupled with a 
radionuclide component (or an antibody component intended solely to be 
coupled with a radionuclide) in which both components provide a 
pharmacological effect but the biological component determines the site 
of action, shall submit a biologics license application to the 
Director, Center for Biologics Evaluation and Research, Food and Drug 
Administration, except if, as determined by FDA, there are significant 
scientific issues associated with the radionuclide or other chemically 
synthesized component, in which case a new drug application shall be 
submitted to the Center for Drug Evaluation and Research, Food and Drug 
Administration;
    (2) An applicant for a radioactive biological product other than as 
described in paragraph (b)(1) of this section, shall submit a new drug 
application to the Center for Drug Evaluation and Research, Food and 
Drug Administration.
    (c)(1) To obtain marketing approval for a biological product 
subject to licensure which is a therapeutic DNA plasmid product, 
therapeutic synthetic peptide product of 40 or fewer amino acids, 
monoclonal antibody product for in vivo use, or therapeutic recombinant 
DNA-derived product, an applicant shall submit a biologics license 
application in accordance with paragraph (a) of this section except 
that the following sections in parts 600 through 680 of this chapter 
shall not be applicable to such products: Secs. 600.10(b) and (c), 
600.11, 600.12, 600.13, 610.11, 610.53, and 610.62 of this chapter.
    (2) To the extent that the requirements in this paragraph (c) 
conflict with other requirements in this subchapter (except for those 
products described in paragraph (b) of this section for which a new 
drug application is required), this paragraph (c) shall supersede other 
requirements.
    (d) Approval of a biologics license application or issuance of a 
biologics license shall constitute a determination that the 
establishment(s) and the product meet applicable requirements to ensure 
the continued safety, purity, and potency of such products. Applicable 
requirements for the maintenance of establishments for the manufacture 
of a product subject to this section shall include but not be limited 
to the good manufacturing practice requirements set forth in parts 210, 
211, 600, 606, and 820 of this chapter.
    (e) Any establishment and product license for a biological product 
issued under section 351 of the Public Health Service Act (42 U.S.C. 
201 et seq.) that has not been revoked or suspended as of December 20, 
1999, shall constitute an approved biologics license application in 
effect under the same terms and conditions set forth in such product 
license and such portions of the establishment license relating to such 
product.


Sec. 601.3   [Removed]

    35. Section 601.3 License forms is removed.
    36. Section 601.4 is amended by revising paragraph (a) and the 
first sentence of paragraph (b) to read as follows:


Sec. 601.4   Issuance and denial of license.

    (a) A biologics license shall be issued upon a determination by the 
Director, Center for Biologics Evaluation and Research that the 
establishment(s) and the product meet the applicable requirements 
established in this chapter. A biologics license shall be valid until 
suspended or revoked.
    (b) If the Commissioner determines that the establishment or 
product does not meet the requirements established

[[Page 56451]]

in this chapter, the biologics license application shall be denied and 
the applicant shall be informed of the grounds for, and of an 
opportunity for a hearing on, the decision. * * *
    37. Section 601.5 is revised to read as follows:


Sec. 601.5   Revocation of license.

    (a) A biologics license shall be revoked upon application of the 
manufacturer giving notice of intention to discontinue the manufacture 
of all products manufactured under such license or to discontinue the 
manufacture of a particular product for which a license is held and 
waiving an opportunity for a hearing on the matter.
    (b)(1) The Commissioner shall notify the licensed manufacturer of 
the intention to revoke the biologics license, setting forth the 
grounds for, and offering an opportunity for a hearing on the proposed 
revocation if the Commissioner finds any of the following:
    (i) Authorized Food and Drug Administration employees after 
reasonable efforts have been unable to gain access to an establishment 
or a location for the purpose of carrying out the inspection required 
under Sec. 600.21 of this chapter,
    (ii) Manufacturing of products or of a product has been 
discontinued to an extent that a meaningful inspection or evaluation 
cannot be made,
    (iii) The manufacturer has failed to report a change as required by 
Sec. 601.12 of this chapter,
    (iv) The establishment or any location thereof, or the product for 
which the license has been issued, fails to conform to the applicable 
standards established in the license and in this chapter designed to 
ensure the continued safety, purity, and potency of the manufactured 
product,
    (v) The establishment or the manufacturing methods have been so 
changed as to require a new showing that the establishment or product 
meets the requirements established in this chapter in order to protect 
the public health, or
    (vi) The licensed product is not safe and effective for all of its 
intended uses or is misbranded with respect to any such use.
    (2) Except as provided in Sec. 601.6 of this chapter, or in cases 
involving willfulness, the notification required in this paragraph 
shall provide a reasonable period for the licensed manufacturer to 
demonstrate or achieve compliance with the requirements of this 
chapter, before proceedings will be instituted for the revocation of 
the license. If compliance is not demonstrated or achieved and the 
licensed manufacturer does not waive the opportunity for a hearing, the 
Commissioner shall issue a notice of opportunity for hearing on the 
matter under Sec. 12.21(b) of this chapter.
    38. Section 601.6 is revised to read as follows:


Sec. 601.6   Suspension of license.

    (a) Whenever the Commissioner has reasonable grounds to believe 
that any of the grounds for revocation of a license exist and that by 
reason thereof there is a danger to health, the Commissioner may notify 
the licensed manufacturer that the biologics license is suspended and 
require that the licensed manufacturer do the following:
    (1) Notify the selling agents and distributors to whom such product 
or products have been delivered of such suspension, and
    (2) Furnish to the Director, Center for Biologics Evaluation and 
Research, complete records of such deliveries and notice of suspension.
    (b) Upon suspension of a license, the Commissioner shall either:
    (1) Proceed under the provisions of Sec. 601.5(b) of this chapter 
to revoke the license, or
    (2) If the licensed manufacturer agrees, hold revocation in 
abeyance pending resolution of the matters involved.
    39. Section 601.9 is revised to read as follows:


Sec. 601.9   Licenses; reissuance.

    (a) Compliance with requirements. A biologics license, previously 
suspended or revoked, may be reissued or reinstated upon a showing of 
compliance with requirements and upon such inspection and examination 
as may be considered necessary by the Director, Center for Biologics 
Evaluation and Research.
    (b) Exclusion of noncomplying location. A biologics license, 
excluding a location or locations that fail to comply with the 
requirements in this chapter, may be issued without further application 
and concurrently with the suspension or revocation of the license for 
noncompliance at the excluded location or locations.
    (c) Exclusion of noncomplying product(s). In the case of multiple 
products included under a single biologics license application, a 
biologics license may be issued, excluding the noncompliant product(s), 
without further application and concurrently with the suspension or 
revocation of the biologics license for a noncompliant product(s).


Sec. 601.10   [Removed]

    40. Section 601.10  Establishment licenses; issuance and conditions 
 is removed.
    41. Section 601.20 is revised to read as follows:


Sec. 601.20   Biologics licenses; issuance and conditions.

    (a) Examination--compliance with requirements. A biologics license 
application shall be approved only upon examination of the product and 
upon a determination that the product complies with the standards 
established in the biologics license application and the requirements 
prescribed in the regulations in this chapter including but not limited 
to the good manufacturing practice requirements set forth in parts 210, 
211, 600, 606, and 820 of this chapter.
    (b)  Availability of product. No biologics license shall be issued 
unless:
    (1) The product intended for introduction into interstate commerce 
is available for examination, and
    (2) Such product is available for inspection during all phases of 
manufacture.
    (c)  Manufacturing process--impairment of assurances. No product 
shall be licensed if any part of the process of or relating to the 
manufacture of such product, in the judgment of the Director, Center 
for Biologics Evaluation and Research, would impair the assurances of 
continued safety, purity, and potency as provided by the regulations 
contained in this chapter.
    (d) Inspection--compliance with requirements. A biologics license 
shall be issued or a biologics license application approved only after 
inspection of the establishment(s) listed in the biologics license 
application and upon a determination that the establishment(s) complies 
with the standards established in the biologics license application and 
the requirements prescribed in applicable regulations.
    (e) One biologics license to cover all locations. One biologics 
license shall be issued to cover all locations meeting the 
establishment standards identified in the approved biologics license 
application and each location shall be subject to inspection by FDA 
officials.
    42. Section 601.21 is revised to read as follows:


Sec.  601.21   Products under development.

    A biological product undergoing development, but not yet ready for 
a biologics license, may be shipped or otherwise delivered from one 
State or possession into another State or possession provided such 
shipment or

[[Page 56452]]

delivery is not for introduction or delivery for introduction into 
interstate commerce, except as provided in sections 505(i) and 520(g) 
of the Federal Food, Drug, and Cosmetic Act, as amended, and the 
regulations thereunder (21 CFR parts 312 and 812).
    43. Section 601.22 is amended by revising the section heading and 
the first and second sentences to read as follows:


Sec. 601.22   Products in short supply; initial manufacturing at other 
than licensed location.

    A biologics license issued to a manufacturer and covering all 
locations of manufacture shall authorize persons other than such 
manufacturer to conduct at places other than such locations the 
initial, and partial manufacturing of a product for shipment solely to 
such manufacturer only to the extent that the names of such persons and 
places are registered with the Commissioner of Food and Drugs and it is 
found upon application of such manufacturer, that the product is in 
short supply due either to the peculiar growth requirements of the 
organism involved or to the scarcity of the animal required for 
manufacturing purposes, and such manufacturer has established with 
respect to such persons and places such procedures, inspections, tests 
or other arrangements as will ensure full compliance with the 
applicable regulations of this subchapter related to continued safety, 
purity, and potency. Such persons and places shall be subject to all 
regulations of this subchapter except Secs. 601.2 to 601.6, 601.9, 
601.10, 601.20, 601.21 to 601.33, and 610.60 to 610.65 of this chapter. 
* * *
    44. Section 601.25 is amended in paragraph (b)(3) under 
``Biological Products Review Information'' by revising section VIII and 
by revising the third sentence of paragraph (f)(3) to read as follows:


Sec. 601.25   Review procedures to determine that licensed biological 
products are safe, effective, and not misbranded under prescribed, 
recommended, or suggested conditions of use.

* * * * *
    (b) * * *
    (3) * * *

BIOLOGICAL PRODUCTS REVIEW INFORMATION

* * * * *
     VIII. If the submission is by a licensed manufacturer, a 
statement signed by the authorized official of the licensed 
manufacturer shall be included, stating that to the best of his or 
her knowledge and belief, it includes all information, favorable and 
unfavorable, pertinent to an evaluation of the safety, 
effectiveness, and labeling of the product, including information 
derived from investigation, commercial marketing, or published 
literature. If the submission is by an interested person other than 
a licensed manufacturer, a statement signed by the person 
responsible for such submission shall be included, stating that to 
the best of his knowledge and belief, it fairly reflects a balance 
of all the available information, favorable and unfavorable 
available to him, pertinent to an evaluation of the safety, 
effectiveness, and labeling of the product.
* * * * *
    (f) * * *
    (3) * * * Where the Commissioner determines that the potential 
benefits outweigh the potential risks, the proposed order shall provide 
that the biologics license for any biological product, falling within 
this paragraph, will not be revoked but will remain in effect on an 
interim basis while the data necessary to support its continued 
marketing are being obtained for evaluation by the Food and Drug 
Administration. * * *
* * * * *
    45. Section 601.26 is amended by revising the second sentence of 
the introductory text of paragraph (e), the first, fifth, and sixth 
sentences of paragraph (f)(1), the second sentence of paragraph (f)(2), 
and the first sentence of paragraph (f)(3) to read as follows:


Sec. 601.26   Reclassification procedures to determine that licensed 
biological products are safe, effective, and not misbranded under 
prescribed, recommended, or suggested conditions of use.

* * * * *
    (e) * * * Where the Commissioner determines that there is a 
compelling medical need and no suitable alternative therapeutic, 
prophylactic, or diagnostic agent for any biological product that is 
available in sufficient quantities to meet current medical needs, the 
final order shall provide that the biologics license application for 
that biological product will not be revoked, but will remain in effect 
on an interim basis while the data necessary to support its continued 
marketing are being obtained for evaluation by the Food and Drug 
Administration. * * *
    (f)  Additional studies and labeling. (1) Within 60 days following 
publication of the final order, each licensed manufacturer for a 
biological product designated as requiring further study to justify 
continued marketing on an interim basis, under paragraph (e) of this 
section, shall submit to the Commissioner a written statement intended 
to show that studies adequate and appropriate to resolve the questions 
raised about the product have been undertaken. * * * The Commissioner 
may extend this 60-day period if necessary, either to review and act on 
proposed protocols or upon indication from the licensed manufacturer 
that the studies will commence at a specified reasonable time. If no 
such commitment is made, or adequate and appropriate studies are not 
undertaken, the biologics license or licenses shall be revoked.
    (2) * * * If the progress report is inadequate or if the 
Commissioner concludes that the studies are not being pursued promptly 
and diligently, or if interim results indicate the product is not a 
medical necessity, the biologics license or licenses shall be revoked.
    (3) Promptly upon completion of the studies undertaken on the 
product, the Commissioner will review all available data and will 
either retain or revoke the biologics license or licenses involved. * * 
*
* * * * *
    46. Section 601.51 is amended by revising the section heading, the 
first sentence of paragraph (a), and paragraph (b) to read as follows:


Sec. 601.51   Confidentiality of data and information in applications 
for biologics licenses.

    (a) For purposes of this section the biological product file 
includes all data and information submitted with or incorporated by 
reference in any application for a biologics license, IND's 
incorporated into any such application, master files, and other related 
submissions. * * *
    (b) The existence of a biological product file will not be 
disclosed by the Food and Drug Administration before a biologics 
license application has been approved unless it has previously been 
publicly disclosed or acknowledged. The Director of the Center for 
Biologics Evaluation and Research will maintain a list available for 
public disclosure of biological products for which a license 
application has been approved.
* * * * *

PART 607--ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR 
MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS

    47. The authority citation for 21 CFR part 607 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 355, 360, 371, 374; 42 
U.S.C. 216, 262.

    48. Section 607.20 is amended by revising paragraph (b) to read as 
follows:


Sec. 607.20   Who must register and submit a blood product list.

* * * * *
    (b) Preparatory to engaging in the manufacture of blood products, 
owners

[[Page 56453]]

or operators of establishments who are submitting a biologics license 
application to manufacture blood products are required to register 
before the biologics license application is approved.
* * * * *
    49. Section 607.21 is amended by revising the second sentence to 
read as follows:


Sec. 607.21   Times for establishment registration and blood product 
listing.

     * * * If the owner or operator of the establishment has not 
previously entered into such operation (defined in Sec. 607.3(d) of 
this chapter) for which a license is required, registration shall 
follow within 5 days after the submission of a biologics license 
application in order to manufacture blood products. * * *

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

    50. The authority citation for 21 CFR part 610 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 
U.S.C. 216, 262, 263, 263a, 264.

    51. Section 610.13 is amended by revising the introductory 
paragraph and the first sentence of paragraph (a)(1) to read as 
follows:


Sec. 610.13   Purity.

    Products shall be free of extraneous material except that which is 
unavoidable in the manufacturing process described in the approved 
biologics license application. In addition, products shall be tested as 
provided in paragraphs (a) and (b) of this section.
    (a)(1) Test for residual moisture. Each lot of dried product shall 
be tested for residual moisture and shall meet and not exceed 
established limits as specified by an approved method on file in the 
biologics license application. * * *
* * * * *
    52. Section 610.53 is amended by revising paragraph (d) to read as 
follows:


Sec. 610.53   Dating periods for licensed biological products.

* * * * *
    (d)  Exemptions. Exemptions or modifications shall be made only 
upon written approval, in the form of a supplement to the biologics 
license application, issued by the Director, Center for Biologics 
Evaluation and Research.
    53. Section 610.63 is revised to read as follows:


Sec. 610.63   Divided manufacturing responsibility to be shown.

    If two or more licensed manufacturers participate in the 
manufacture of a biological product, the name, address, and license 
number of each must appear on the package label, and on the label of 
the container if capable of bearing a full label.

 PART 640--ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS

    54. The authority citation for 21 CFR part 640 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 
U.S.C. 216, 262, 263, 263a, 264.

    55. Section 640.6 is amended by revising the introductory text to 
read as follows:


Sec. 640.6   Modifications of Whole Blood.

    Upon approval by the Director, Center for Biologics Evaluation and 
Research, of a supplement to the biologics license application for 
Whole Blood a manufacturer may prepare Whole Blood from which the 
antihemophilic factor has been removed, provided the Whole Blood meets 
the applicable requirements of this subchapter and the following 
conditions are met:
* * * * *
    56. Section 640.21 is amended by revising paragraph (c) to read as 
follows:


Sec. 640.21   Suitability of donors.

* * * * *
    (c) Plateletpheresis donors shall meet criteria for suitability as 
described in a biologics license application or a supplement to the 
biologics license application, and must have the written approval of 
the Director, Center for Biologics Evaluation and Research, Food and 
Drug Administration.
    57. Section 640.22 is amended by revising paragraph (c) to read as 
follows:


Sec. 640.22   Collection of source material.

* * * * *
    (c) If plateletpheresis is used, the procedure for collection shall 
be as described in a biologics license application or a supplement to a 
biologics license application, and must have the written approval of 
the Director, Center for Biologics Evaluation and Research, Food and 
Drug Administration.
* * * * *
    58. Section 640.64 is amended by revising the second sentence of 
the introductory text of paragraph (c) to read as follows:


Sec. 640.64   Collection of blood for Source Plasma.

* * * * *
    (c) * * * One of the following formulas shall be used in the 
indicated volumes, except that a different formula may be used for 
plasma for manufacture into noninjectable products if prior written 
approval is obtained from the Director of the Center for Biologics 
Evaluation and Research at the time of licensing or in the form of a 
supplement to the biologics license application for Source Plasma.
* * * * *
    59. Section 640.65 is amended by revising the last sentence of 
paragraph (a) to read as follows:


Sec. 640.65   Plasmapheresis.

    (a) * * * This procedure shall be described in detail in the 
biologics license application.
* * * * *
    60. Section 640.71 is amended by revising the introductory text of 
paragraphs (a) and (b) and by revising paragraph (b)(1) to read as 
follows:


Sec. 640.71   Manufacturing responsibility.

    (a) All steps in the manufacture of Source Plasma, including donor 
examination, blood collection, plasmapheresis, laboratory testing, 
labeling, storage, and issuing shall be performed by personnel of the 
licensed manufacturer of the Source Plasma, except that the following 
tests may be performed by personnel of a manufacturer licensed for 
blood or blood derivatives under section 351(a) of the Public Health 
Service Act, or by a clinical laboratory that meets the standards of 
the Clinical Laboratories Improvement Act of 1967 (CLIA) (42 U.S.C. 
263a): Provided, The establishment or the clinical laboratory is 
qualified to perform the assigned test(s).
* * * * *
    (b) Such testing shall not be considered divided manufacturing, 
which requires two biologics licenses for Source Plasma: Provided, That
    (1) The results of such tests are maintained by the licensed 
manufacturer of the Source Plasma whereby such results may be reviewed 
by a licensed physician as required in Sec. 640.65(b)(2) of this 
chapter and by an authorized representative of the Food and Drug 
Administration.
* * * * *
    61. Section 640.74 is amended by revising paragraph (a) and the 
last sentence of paragraph (b)(2) to read as follows:

[[Page 56454]]

Sec. 640.74   Modification of Source Plasma.

    (a) Upon approval by the Director, Center for Biologics Evaluation 
and Research, Food and Drug Administration, of a supplement to the 
biologics license application for Source Plasma, a manufacturer may 
prepare Source Plasma as a liquid product for a licensed blood 
derivative manufacturer who has indicated a need for a liquid product.
    (b) * * *
    (2) * * * Such evidence may be submitted by either the licensed 
manufacturer of the Source Plasma Liquid or the manufacturer of the 
final blood derivative product who has requested the Source Plasma 
Liquid.
* * * * *

 PART 660--ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR 
LABORATORY TESTS

    62. The authority citation for 21 CFR part 660 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 
U.S.C. 216, 262, 263, 263a, 264.

    63. Section 660.21 is amended by revising paragraphs (a)(3) and (d) 
to read as follows:


Sec. 660.21   Processing.

    (a) * * *
    (3) A lot may be subdivided into clean, sterile vessels. Each 
subdivision shall constitute a sublot. If lots are to be subdivided, 
the manufacturer shall include this information in the biologics 
license application. The manufacturer shall describe the test 
specifications to verify that each sublot is identical to other sublots 
of the lot.
* * * * *
    (d)  Volume of final product. Each manufacturer shall identify the 
possible final container volumes in the biologics license application.
* * * * *
    64. Section 660.30 is amended by revising paragraph (b) to read as 
follows:


Sec. 660.30   Reagent Red Blood Cells.

* * * * *
    (b)  Source. Reagent Red Blood Cells shall be prepared from human 
peripheral blood meeting the criteria of Secs. 660.31 and 660.32 of 
this chapter, or from umbilical cord cells which shall be collected and 
prepared according to the manufacturer's biologics license application.
    65. Section 660.33 is amended by revising the fifth sentence to 
read as follows:


Sec. 660.33   Testing of source material.

    * * * Where fewer than three donor sources of an antibody 
specificity are available, test discrepancies shall be resolved in 
accordance with the manufacturer's biologics license application. * * *

    Dated: August 30, 1999.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 99-27159 Filed 10-19-99; 8:45 am]
BILLING CODE 4160-01-F